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Rapid Electrochemical Conversion of Thiol and Disulfide into Difluoro and Trifluoromethyl Thioethers in a Microfluidic Reactor

[ Vol. 4 , Issue. 3 ]

Author(s):

Kenta Arai *, Setsura Ueda and Sayaka Tamura   Pages 137 - 143 ( 7 )

Abstract:


Background: Difluoro- and trifluoromethyl thioethers, i.e., –SCHF2 and –SCF3, which have strong electron-withdrawing effects and extremely high lipophilicities, have recently received interest because of their pharmacological and agrochemical applications.

Methods: Here, we developed a novel synthetic methodology for SCHF2 and SCF3 compounds using an electrochemical microreactor (ECMR), which enables flash electrochemical reactions because of the intrinsic short diffusion distances. A mixed solution containing the disulfide or thiol substrate, triethylamine, and difluoro- or trifluoroacetic acid, which release CF3 and CHF2 radicals by Kolbe electrolysis, was electrolyzed using a constant current under microfluidic conditions. The disulfide or thiol substrate (e.g., cystine or cysteine derivative) was converted into the corresponding SCHF2 and SCF3 compound or their sulfoxide forms within 30 s; however, aromatic thiols/disulfides and tert- and secthiols/ disulfides were not suitable in this synthesis. All the flow reactions progressed under mild conditions without any catalysts or redox reagents and using traditional CF3 and CHF2 sources, which are generally expensive and hazardous. In addition, the ECMR technology could successfully be applied to direct conversion of cysteinyl thiol in the glutathione derivative (a tripeptide with a γGlu–Cys–Gly sequence) into SCF3 and SCHF2 groups.

Results: The results suggest that the ECMR is a powerful and an environmentally friendly tool in the development of small organic molecule and peptide-based drugs containing –SCHF2 and –SCF3 moieties.

Keywords:

Difluoromethyl thioether, electrochemical synthesis, flow chemistry, kolbe electrolysis, microreactor, peptide, trifluoromethyl thioether.

Affiliation:

Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa 259-1292

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